The present invention pertains to aerosol formulations of drugs, such as those formulations suitable for use in pressurized aerosol metered dose inhalers.
Aerosolized drugs have been used for many years to treat disorders of the respiratory system, and as a convenient means for the systemic introduction of various pharmaceutical agents into the body. The typical aerosol formulation in a metered dose inhaler for treating disorders such as asthma or rhinitis is a suspension of one or more drug substances in a fully halogenated (with chlorine and/or fluorine) lower alkyl compound propellant, further containing small amounts of surfactants and/or excipients which are usually soluble in the propellant. Pharmaceutical agents administered by means of metered dose inhalers are usually bronchodilators or corticosteroids.
Typical formulations contain chlorofluorocarbon propellants, the drug substance and ethanol, which is miscible with the propellant, and sometimes also contain a surfactant such as oleic acid for maintaining a stable suspension, lubrication of the metering valve and other functions.
In general, drug particle sizes from about 1 to about 5 μm are preferred for administration to the lower airway, with particles smaller than about 0.5 μm frequently being exhaled without complete deposition on tissues, while particles larger than about 10 μm can exhibit considerable deposition in the mouth and/or pharynx and therefore not reach the lower airway. Very large particles cannot pass through a metering valve and will not be reliably dispensed.
With the implication of fully halogenated chlorofluorocarbon propellants in the environmentally harmful destruction of ozone in the upper atmosphere, the availability of these propellants has become quite restricted. This has encouraged development work toward formulations containing propellants having reduced upper atmospheric reactivity, such work particularly centering about the propellants HFC 134a and HFC 227, these compounds having approximately the same physical properties as those of the older chlorofluorocarbons used for medicinal aerosols.
Metered dose inhalers typically employ metallic canisters to store the medicament, propellant and excipients. The inner wall of the canister can, for example, be embedded with various plastic coatings, e.g. Teflon. This aids in preventing deposition of the medicament on to the wall.
It is preferable that the inside of the container or can that is in contact with the medicament be as smooth possible. This is so because irregularities in the surface of the container can provide a seed area for the medicament to first lodge or deposit and eventually grow. The process of mass transfer and consequent deposition of the medicament crystals is usually dependent on the crystal size of the medicament, the presence of impurities, and the temperature of the ambient and surface irregularities.
These surface irregularities may provide a locus for the deposition of larger crystals which have higher settling velocities. These would create a “mass transfer” boundary layer where mass transfer proceeds by molecular diffusion. Fluctuations in the ambient temperature, as encountered during shipping and handling, can lead to crystal growth, the activation energy for which is temperature dependent and follows the Arrhenius equation. These “growing” crystals would also remain lodged/deposited on the surface imperfection and thus become unavailable for delivery. Therefore overtime, this phenomenon of can wall deposition can lead to a decrease in the amount of medicament that is dispensed to the patient.
There thus exists a need for dosing systems having canisters with smooth interiors that minimize the possibility of can wall deposition by not providing the locii for crystal deposition such that it is ensured that the patient receives the requisite amount of medication.